Acid sensing ion channel (ASIC) inhibitors exhibit anxiolytic-like activity in preclinical pharmacological models.
BACKGROUND
Acid sensing ion channels (ASICs) are proton-gated ion channels located in the central and peripheral nervous systems. Of particular interest is ASIC1a, which is located in areas associated with fear and anxiety behaviors. Recent reports suggest a role for ASIC1a in preclinical models of fear conditioning and anxiety.


OBJECTIVE
The present experiments evaluated various ASIC inhibitors in preclinical models of autonomic and behavioral parameters of anxiety. In addition, neurochemical studies evaluated the effects of an ASIC inhibitor (A-317567) on neurotransmitter levels in the amygdala.


RESULTS
In electrophysiological studies using hippocampal primary neuronal cultures, three ASIC inhibitors (PcTX-1, A-317567, and amiloride) produced concentration-dependent inhibition of acid-evoked currents. In the stress-induced hyperthermia model, acute administration of psalmotoxin 1 (PcTX-1; 10-56 ng, i.c.v.), A-317567 (0.1-1.0 mg/kg, i.p.), and amiloride (10-100 mg/kg, i.p.) prevented stress-induced elevations in core body temperature. In the four-plate test, acute treatment with PcTX-1 (10-56 ng, i.c.v.) and A-317567 (0.01-0.1 mg/kg, i.p.), but not amiloride (3-100 mg/kg, i.p.), produced dose-dependent and significant increases in the number of punished crossings relative to vehicle-treated animals. Additionally, PcTX-1 (56-178 ng, i.c.v.), A-317567 (0.1-10 mg/kg, i.p.), and amiloride (10-100 mg/kg, i.p.) lacked significant anxiolytic-like activity in the elevated zero maze. In neurochemical studies, an infusion of A-317567 (100 microM) into the amygdala significantly elevated the extracellular levels of GABA, but not glutamate, in this brain region.


CONCLUSIONS
These findings demonstrate that ASIC inhibition produces anxiolytic-like effects in some behavioral models and indicate a potential role for GABAergic mechanisms to underlie these anxiolytic-like effects.
Dwyer
Jason M
JM
Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ, 08543-8000, USA.
Rizzo
Stacey J Sukoff
SJ
Neal
Sarah J
SJ
Lin
Qian
Q
Jow
Flora
F
Arias
Robert L
RL
Rosenzweig-Lipson
Sharon
S
Dunlop
John
J
Beyer
Chad E
CE
D062565:Acid Sensing Ion Channels; D000584:Amiloride / Q000494:pharmacology; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005106:Exploratory Behavior / Q000187:drug effects; D005334:Fever / Q000378:metabolism / Q000517:prevention & control / Q000523:psychology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D009281:Naphthalenes / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010455:Peptides; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000378:metabolism; D013111:Spider Venoms / Q000494:pharmacology; D013315:Stress, Psychological / Q000150:complications / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C506640:A-317567; C568267:ASIC1 protein, mouse; D062565:Acid Sensing Ion Channels; D014151:Anti-Anxiety Agents; D007546:Isoquinolines; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; C413209:PcTX1 protein, Psalmopoeus cambridgei; D010455:Peptides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013111:Spider Venoms; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D000584:Amiloride